Choline and inositol preparation containing a surface-active agent



United States liatent O" Michael R. Maiese, Brooklyn, N. 'Y.,- assignor to American Home Products Corporation, New York, N. Y., a corporation of Delaware No Drawing. Application November 19,1951,

Serial No. 257,173

5 Claims. (Cl. 16755) This invention relates to a choline and inositol preparation containing a surface-active agent.

One of the serious degenerative diseases of present times is hardening of the arteries or arteriosclerosis. Many investigations have been and are being directed to understanding its causes and finding satisfactory means and methods of treatment. In spite of considerable progress-its etiology is not yet completely understood; it appears likely, however, that hardening of the artery walls is preceded by atherosclerosis, or the deposit of cholesterol plaques on the intimae or inner surfaces of the arterial lumen.

Efforts have been made to prevent or alleviate this condition by utilizing the known lipotropic action of choline. This has been used in conjunction with inositol (i-inositol) because of the known favorable effect of inositol on the linotropic action of choline. .(The Biochemistry of inositol, E. R. Weidlein, In, Mellon Institute. Pittsburgh, Pa., l95l, page 27.) As far as I know, none'iof these attempts have yielded certain and consistently. satisfactory resul ts."- See, for example, Herrmann, (inks-Texas State J. of Med. 42, 260-263 (1946) and Queries and Minor N otes,.J. A. M. A., September 8, l95l, -vol.-l47, No. 2. page 205.

An indication of incipient or active atherosclerosis is a high cholesterol blood level. While the cholesterol blood level in normal individuals varies within wide limifsg if it exceeds 300 mg. percent, danger of atherosclerosis is indicated. There is, however, one qualifying factor, namely.pthe'ratio of phosphatidesto cholesterol in the blood. If this ratio is greater than 1. a somewhat higher cholesterol level can, it is believed, be tolerated without adverse effect.

It is the obiect of this invention to provide a theraeutic composition effective in reducing the cholesterol blood level and in producing a phosphatidetcholesterol has the ability. when administered orally, to reduce ab- 1 Oil of orange (terpeneless) 2,594,664 Patented Nov. 16 19 54 ice tion containing choline, preferablya'sa salt such as the di-hydrogen citrate, a non-toxrc'surface-active agent and inositol. Such a solution is. intended for oral'administration and I have found it convenient to use concentrations yielding one dose per teaspoonful (5 nth). I maytalso introduce glycerol to prevent gelling andreduce viscosity, flavoring-materials such as ,:sucrose and oil of orange, and preservatives such as sodium benzoate and sodium propionate; these ingredients while usually desirable, are not essential. V t

A preferred surface-actives nt for use in my preps.- ration is polyoxyethylene sor itau monooleate (e. g. Tween produced by the Atlas Powder Company). This product is satisfactory because .(a) of its proved non-toxicity, (b) of its favorable; hydrophilic-lipophilic balance, and (c) it gives optically clear solutions to the naked eye. Other surface-active agents, however, may be substituted and the clarity of the solution is more of an esthetic than practical requirement provided there is no actual settling of sediment. Among other usable surface-active agents are:

Non-ionic:

Polyoxyethylene sorbitan monolaurate (Tween 20) (Atlas). Polyoxyethylene sorbitan I trioleate (Tween (Atlas).

Polyoxyethylene sorbitol I pentaoleatc a; (Atlas).;

One preferred embodiment of. inventionfhas :the

following composition:. Choline di-hydrogen citrate (equivalent to 4.10 g.

Sodium saccharin Sucrose (starch-free) Sodium 'benzoate 7 Sodium .propionate NaOH. to approximately Water to=l00-ml.

This 'prepara tion, isa clear, l1

hi aibeiirentiviyabnlviscous liquid, of pleasant 'tastefwhich disperses rapidly,

normally high bloodcholester'ol levels and to increase I to ha e been established that choline and inositol alone are effective in many cases in defatting fatty livers. (Pollak, Geriatics. September-October 1951, p. 309.) According to Pollaks theory. the alleviation of atherosclerosis is primarily due to this defatting action. which restores the liver to normal functioning.

It has also been established that the surface-active agent polyoxycthylene sorbitan monooleate (Tween 80." Atlas Powder Company) is a very effective agent in increasing fat absorption and does not affect blood cholesterol levels. (Krantz et 21].. Bull. School of Med. Univ. of Md., 36 (1951), 48-56.) V

In view of these facts it is surprising and unexpected that in my compositions a surface-active agent which facilitates fat absorption should greatly augment the boneficial effects of choline and inositol in reducing the blood cholesterol level and make this combination a reliable therapeutic agent for treating hypcrchnlestcremia and thus alleviating atherosclerosis.

According to my invention I provide an aqueous solulit hibit fermentation and mold growth '2 palatability limits. range from 3 to 7;

in the saliva. when 'takdorally. Itj'Wilfprovide a dose of 0.5 g. choline iii-hydrogen citrate (0.2 g. choline base) and 0.25 g. inositol and 0.5 g. Tween 80 per teaspoon-t. to] (5 ml.-)." it has good shelf life; "As pointedour above, theessential ingredients are the choline, inositol and surface-active agents glycerol reduces viscosity, the saccharin, sncrose and Oil of orange are added-for flavor, and the benzoate'andpropionate respectively in- ThepH is adjusted to a favorable value for stability and palatability. While each ingredient has a specific. function J in providing a preparation of pleasant consistency and taste andof good shelf life, from the physiological point of view the, glycerol, the flavoring materials, the pH adjustment may be omitted wi out seriously impairing the etiicacy of the preparation.

The relative amounts of the ingredients may be varied considerably from the abovelisted. amounts, provided they are kept within appropriate solubility limits. The Tween 80 may vary from about 10 g. to about 40 g. per ml. of preparation depending on the concentration of the cholinesalt used. The choline base and inositol may be reduced to any desired therapeutic minimum and may be respectively as high as 25 g. and 12.5 g. or more per 100 ml. The flavoring materials and preservatives may obviously be widely varied, omitted or re placed by substitutes, and the pH may, within reasonable .The choline ma be present as thefree base, or other salts than the drhydrogen citrate may be used, e. g. the hydrochloride, the tricilrnte, the bitartrate.

In making up my preparation I prefer to dissolve the choline or choline salt, inositol, saccharin, sucrose and sodium benzoate and propionate in water, e. g. 36 ml.

reservatives andv the water, with gentle warming, and then add the glycerol. I then separately dissolve the oil of orange in the Tween 80." I mix the two solutions, bring them to pH 4 with a -small amount of 50 percent NaOI-I, and finally dilute with water to 100 ml.

My preparation may also be given in capsule form, the capsule containing only choline or a choline salt, inositol and surface-active agent. Each capsule may, for example, contain 0.25 g. choline di-hydrogen citrate 0.125 g. inositol and 0.25 g. surface-active agent.

In therapeutic use my preferred compound, described above, is usually administered in divided doses of three to four teaspoonfuls per day, providing approximately 0.6 g. to 0.8 g. choline base, 0.75 g. to 1.0 g. inositol and 1.5 g. to 2.0 g. Tween 80" per day. This course of treatment usually lasts for one or two weeks, after which a maintenancedosage regime may be followed or medication may be stopped altogether, depending on the reaction of the patient. In some cases the reduced blood cholesterol level is maintained for considerable periods without maintenance medication, and in some cases. especially where complications are involved. a longer period of administration is required.

The results obtained by the administration of my pre ferred composition described above to four hypercholest'eremic patients are tabulated on the following pages. They may be considered typical.

Linnld Phospha- Blom Phospha- Duration of Obscr- Cholesterol, 2 5 tide! vation, days m2. mg {a Cholesterol percent percent Pxzs) Ratio CASE 1 Llpold Phospha- Blood Phospha- Durstlon ol Obser- Cholesterol, g' f' tlde/ vatlon, days mg. p m 2 id Cholesterol percent gr Ratio percent PX) 321.1 7. so i 195 0.61

.ledlcati-n started 315 9 8. 82 221 0. 70 176. 8 & 81 220 l. 24

Left ospital: ct'lcatlon contained 204. l 7. 80 195 0.96. 28. 224. 9 9. 16 229 l. 02 211 9 9 57 l. 13

239 Medication consisted of l tesspooniul of my preferred composition 4 times daily I CASE 2 edloation started 346. 2 10. 87 l 272 0. 7i! 335. 7 ll. 77 294 0. 87

. Left h pital; meditation stopped edieatton as In Case 1 CASE 3 Medleatinn started 337. 4 3 58 215 0. 64 254. 8 8. 84 221 0. 87 292. 5 l0. 4 200 t). 89 262. 6 11. 4 285 1.09 Discharged from hospital; Medication as in Caso 1 CASE 4 300.1 i s. an m I 0. r4

Medication stnrtul 256. l 9. 57 234 (J. 91 215. 8 11.4, 285 1.32 Discharged to (hronlc "1868MB ospltal These patients were selected for treatment because they were diabetic and consequently prone to hyperlipcmia and subsequent atherosclerosis. Cases 1, 2 and 3 2 for 20 days after discontinuance of medication.

had blood cholesterol levels well above the normal maximum of 300 mg. percent. While the cholesterol level of Case 4 was substantially 300, the low ratio of phosphatide to total cholesterol indicated treatment. In all cases a substantial reduction of blood cholesterol was achieved; in Case 1 this was noted after 14 days of medication, in Case 2 after 8 days, in Case 3 after 14 days and in Case 4 after 11 days. The improvement was maintained during the period of observation, in Case n all cases the circulatory condition of the patients was improved. I

In all cases also the phosphatide level was increased and the phosphatidewholcsterol ratio was raised to l or more. This is considered remarkable in view of the usual stability and constancy of the human blood phosphatide levels.

Treatment of numerous other patients has yielded similar results.

- used in its broad sense to include choline base and the therapeutic salts of choline unless otherwise specified. The. term dissolved is used in a broad sense to include colloidal as well as molecular solution.

I claim:

l. A therapeutic preparation for oral administration which comprises an aqueous solution containing inositol, choline in a therapeutically-effective concentration, and a surface active agent comprising a polyoxyethylene sorbitan higher fatty acid ester dissolved therein, said surface active agent being present in an amount rang ing from about 10 grams to about 40 grams for each milliliters of solution. 1

2. A therapeutic preparation for oral administration which comprises an aqueous solution containing choline and inositol in a therapeutically-effective concentration and a surface active agent comprising polyoxyethylene sorbitan monooleate dissolved therein, said surface active agent being present in an amount ranging from about 10 grams to about 40 grams for each 100 millilitersof solution.

3. A therapeutic preparation for oral administration which comprises an aqueous solution containing choline and inositol in a therapeutically-effective concentration and a surface active agent comprising polyoxyethylene sorbitan monolaurate dissolved therein, said surface active agent being present in an amount ranging from about 10 grams to about 40 grams for each 100 mil liliters of solution.

4. A therapeutic preparation for oral administration which comprises an aqueous solution containing choline and inositol in a therapeutically-effective concentration and a surface active agent comprising polyoxyethylene sorbitan trioleate dissolved therein, said surface active agent being present in an amount ranging from about 10 grams to about 40 grams for each 100 milliliters of solution.

5. A therapeutic preparation for oral administration which consists of a capsule containing a therapeutic amount of choline and inositol and 0.25-0.7 g. of a polyoxyethylene sorbitan higher fatty acid ester.

References Cited in the file of this patent UNITED STATES PATENTS Number 'Name Date 2,407,624 Bird Sept. 17, 1946 2,417,299 Freedman Mar. 11, 1947 OTHER REFERENCES U. S. Dispensatory, 24th ed. (1947), pp. 1400, 1401, 1488, 1489. 

1. A THERAPEUTIC PREPARATION FOR ORAL ADMINISTRATION WHICH COMPRISES AN AQUEOUS SOLUTION CONTAINING INOSITOL, CHLORINE IN A THERAPEUTICALLY-EFFECTIVE CONCENTRATION, AND A SURFACE ACTIVE AGENT COMPRISING A POLYOXYETHYLENE SORBITAN HIGHER FATTY ACID ESTER DISSOLVED THEREIN, SAID SURFACE ACTIVE AGENT BEING PRESENT IN AN AMOUNT RANGING FROM ABOUT 10 GRAMS TO ABOUT 40 GRAMS FOR EACH 100 MILLILITERS OF SOLUTION. 